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TitleAn Intro. to Vascular Bio. - From Basic Sci. to Clin. Pract. 2nd ed. - B. Hunt et. al., (Cambridge, 2002) WW
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Page 1

An Introduction to Vascular Biology
Second edition

Vascular biology is an exciting and rapidly advancing area of medical research, with many new

and emerging pathophysiological links to an increasing number of diseases. This updated and

expanded new edition takes full account of these developments and conveys the basic science

underlying a wide range of clinical conditions, including atherosclerosis, hypertension, diabetes

and pregnancy. As with the Wrst edition, the publication provides an introductory account of

vascular biology before leading on to explain mechanisms involved in disease processes. Other

emerging topics include the role of nitric oxide and apoptosis in vascular biology. The breadth

and range of subjects covered in this new edition do full justice to this increasingly important

area of clinical research and medicine. This multidisciplinary approach will suit the needs of all

those who are new to the Weld or working in one small area, with a need to get the wider picture,

and also for those seeking to refresh their knowledge with the very latest advances from basic

science through to clinical practice.

Features of the new edition

∑ All chapters fully updated and expanded, including up-to-date references

∑ Includes several new clinical chapters

∑ Covers new and emerging areas of research

∑ Integrates basic science and clinical practice

Reviews of the Wrst edition

‘I recommend this book to those seeking an introductory overview into this exciting and rapidly

burgeoning area. The authors provide an up-to-date interpretation of vascular biology and how

this might relate to disease; the Wgures are excellent; and the references oVer access to further

sources of information.’ journal of the royal society of medicine

‘. . . it makes excellent reading . . . for readers who are interested in gaining fundamental

understanding of this critical area. I believe the book oVers an excellent pathway towards this

goal.’ british journal of surgery

‘It is well written, with the correct balance of Wgures, tables and text, and also well referenced . . .

I warmly recommend it.’ biomedical sciences

Page 2

MMMM

Page 235

222 N. Chan and P. Vallance

histamine) and platelet-derivedmediators (such as serotonin and adenine diphos-
phate). SpeciWc receptors for these stimuli mediate eNOS activation through

coupling with G proteins (e.g. serotonin receptors; Boulanger and Vanhoutte,

1997). Inhibition of eNOS activities may also be induced by the association of
eNOS with caveolin-1 and caveolin-3 in endothelial cells and myocytes respective-

ly (Garcia-Cardena et al., 1997). This negative eVect on eNOS activities may be a

result of interference with calcium/calmodulin binding and electron transfer
(Ghosh et al., 1998). Thus the balance between activation and inhibition mechan-

isms mediated by various receptors and caveolin regulates eNOS activity.

Genetic variation in NOS isoforms

The genetic sequence and chromosomal location for each of the NOS isoforms in

human have been identiWed (Wang and Marsden, 1995). There is signiWcant
genetic sequence variation for eNOS between individuals (Nadaud et al., 1994;

Wang et al., 1996; Markus et al., 1998; Miyamoto et al., 1998; Hingorani et al.,

1999). Recently, it has been shown that one eNOS gene polymorphism involves a
point mutation (G�T subsitution) in exon 7 of the gene which predicts an

amino acid substitution, glutamic acid � aspartic acid at residue 298 of the

mature protein (Yoshimura et al., 1998; Hingorani et al., 1999). The Asp/Asp
protein is more susceptible to proteolytic degradation. In some studies, this

mutation has been associated with essential hypertension (Miyamoto et al., 1998),

coronary artery disease (Cai et al., 1999; Hingorani et al., 1999; Liao et al., 1999)
and acute myocardial infarction (Hibi et al., 1998; Shimasaki et al., 1998) but

further studies are needed. Additional genetic polymorphism involving mutations

in the 5'-Xanking region of the eNOS gene (T-786�C) has been demonstrated
and appears more prevalent in Japanese patients with coronary spasm. This

mutation results in a signiWcant reduction in eNOS gene promotor activity leading

to reduced eNOS expression, at least in vitro (Nakayama et al., 1999). Polymor-
phism of the variable number of tandem repeats (VNTR) in intron 4 of the eNOS

gene was found to contribute to variation in fasting plasma levels of NO in healthy

human subjects and with a variety of cardiovascular diseases (Wang et al., 1997).
However, its functional signiWcance is uncertain since in itself it should not aVect

eNOS expression or activity.

Biological effects of NO on the vasculature

Endothelium-derived NO is a very potent vasodilator in the vasculature and the
balance between NO and various endothelium-derived vasoconstrictors (such as

endothelin) and the eVects of the sympathetic nervous system maintains the blood

vessel tone. In addition, NO has antiatherogenic properties including suppression

Page 236

223 Nitric oxide

of platelet aggregation, leukocyte migration and cellular adhesion to the en-
dothelium (Radomski et al., 1987, 1990; Bath et al., 1991; Kubes et al., 1991;

Bode-Boger et al., 1994) and inhibition of VSMC mitogenesis, proliferation (Garg

and Hassid, 1989; Nakaki et al., 1990; Scott-Burden and Vanhoutte, 1993) and
migration (Sarkar et al., 1996). Furthermore, NO inhibits the activation and

expression of certain adhesion molecules (De Caterina et al., 1995; Bi� et al.,
1996; Khan et al., 1996; Takahashi et al., 1996), production of superoxide anion
(Clancy et al., 1992) and oxidation of low-density lipoprotein (LDL) (Hogg et al.,

1993). Loss of endothelium-derived NO would be expected to promote a vascular

phenotype more prone to atherogenesis, a concept supported by studies in
experimental animals (Carvalho et al., 1987; Chataigneau et al., 1999).

Nitric oxide release from the vascular endothelium

There is a continuous basal release of NO from the vascular endothelium to

maintain the resting vascular tone. A number of chemical and physical stimuli
may activate eNOS which leads to increased NO production contributing to the

control and regulation of the vascular tone (Busse et al., 1993).

Basal nitric oxide release

The synthesis of NO in vascular endothelial cells in culture and in fresh vascular

tissue can be inhibited by NG-monomethyl-l-arginine (l-NMMA), an analogue of
l-arginine in which one of the guanidino nitrogen atoms is methylated (Palmer et

al., 1988). This inhibitory e�ect of l-NMMA is readily reversed by l-arginine and
the inactive stereoisomer (d-NMMA) has no e�ect on the l-arginine – NO
pathway (Vallance et al., 1989a). This NOS-inhibitor has been used to examine the

role of NO in various vascular beds in vitro and in vivo in both human and animal

models.
In rings of rabbit aorta, l-NMMA causes signi�cant endothelium-dependent

contraction (Rees et al., 1989a). Intravenous infusion of l-NMMA induced a

dose-related increase in blood pressure which is reversed by intravenous adminis-
tration of l-arginine in guinea pigs (Aisaka et al., 1989), rats (Whittle et al., 1989)

and rabbits (Rees et al., 1989a). These in vitro and in vivo data suggest a pivotal

role of basal NO synthesis in maintaining vascular tone.
In the human forearm vasculature, infusion of l-NMMA via the brachial artery

causes substantial dose-dependent vasoconstriction, indicating that continuous

generation of NO is crucial in maintaining peripheral vasodilatation (Figure 10.4;
Vallance et al., 1989a). Basal NO production also occurs in every other vascular

bed studied, including cerebral (White et al., 1997), pulmonary (Stamler et al.,

1994), renal (Haynes et al., 1993) and coronary arteries (Lefroy et al., 1993).

Page 470

decreased sensitivity 235

elastin 306

endothelium-derived NO 217

�brous cap 306
growth factors 306

matrix proteins 306

matrix synthesis stimulation 308

migration 305, 306, 308

mitomycin-C 152

nerve in�uences 82, 84
oestrogen receptors 41

plaque

rupture 308

stability 306–8

potassium channels 73

proliferation 308

repair

phenotype 306

stimulation 313

role 306

synthetic phenotype 306

vessel wall 116–18

wound-healing response 305

vascular structural change reversibility 295–6

vascular tone 3–26

catecholamines 73–5

chronic heart failure 231

�ow 49–51
hormones 71–2

neural control 80

neurohumoral regulation 70–88

eNOS-derived nitric oxide 226

pregnancy 399

sympathetic nerve �ring activity 86
vasoactive agents 71–2

vascular wall

cell proliferation/death 116–18
compliance 277

disease prediction/prevention 276–7

hypervascularity with thrombus 275

magnetic resonance imaging 266–75

neovascularity with thrombus 275

NO-dependent signalling 219

remodelling 116

sti�ness 277
structure 37–8

remodelling 37, 39–40

tension and angiogenesis initiation 96

thickening calculation 280

ultrasound 272–3

see also shear stress

vasculitides/vasculitis 343–56
ANCA-associated systemic 344–9

classi�cation 344, 345
de�nition 343
essential cryoglobulinaemic 344

immune complex-mediated 204

intimal proliferation 343

renal limited 344–5, 347

autoantibodies 354

segmental necrotizing glomerulonephritis 348

small-vessel 343

systemic necrotizing 346

see also Churg–Strauss syndrome; microscopic

polyangiitis; Wegener’s granulomatosis

vasculogenesis 93

vasoactive agents 71–2

vasoactive intestinal peptide (VIP) 4, 80

cotransmitter with acetylcholine 84, 87

vasoconstrictor agents 206, 285, 286

agonists 74

vasoconstrictor nerves 85–6

vasoconstrictors

generation by endothelium 289

small vessel response 293, 294

vasodilatation

�2-adrenoceptors 180
l-arginine 237

endothelially driven 276

endothelium-dependent 224, 231

�ow-mediated in pregnancy 402–3
impaired 229, 286–7, 329, 331–5, 336, 410

�ow-mediated 52–3, 329
insulin 230

nitric oxide 276

endothelium-derived 222

parasympathetic 87

peripheral 401

pregnancy 400, 401

resistance arteries 39

shear stress 276

vasodilator agents 285, 286

vasodilator nerves 86–7

parasympathetic 87

vasodilator response, transient 86–7

vasodilators, endothelium-dependent 405

vasodilatory response 277

vasopressin 4, 73, 75–7

nitric oxide 193

secretion regulation 75–6

457 Index

Page 471

vasorelaxation 227

phVEGF165 104, 105

vein graft disease 129

venography, conventional of Wlling defects 267

venous malformations, autosomal-dominant 109

venous thrombosis, asymptomatic 272

vesicles, prothrombinase activity 196

vesicular monoamine transporter (VMAT) 87

vessel bifurcations, turbulent Xow 276

vimentin Wlaments 392

displacement in response to Xow 54

vimentin recognition by T cells 392–3

vinculin 18

viral infections, endothelial cell activation 188, 203

visual disablement 130

vitamin C 238

preeclampsia 413, 415–16

vitamin E

coronary heart disease 239

preeclampsia 413, 415–16

renal failure 53

smokers 53

vitreoretinopathy, proliferative 130

vitronectin 100

volume homeostasis 399

von Willebrand factor 96–7, 100, 131

diabetes mellitus 328–9

endothelial cells

activation 188, 189, 196

during transplant rejection 385–6, 387

gene expression 209

preeclampsia 410

pregnancy 405

systemic vasculitides 204

Wegener’s granulomatosis 344, 346–7

autoantibodies 354

segmental necrotizing glomerulonephritis 348

Staphylococcus aureus 353

T cells 353

Weibel Palade bodies 190, 196

Western blotting 146

Windkessel eVect 34–5

mathematical model 37

World Health Organization (WHO) pulmonary

hypertension classiWcation 361, 362

wound

inXammatory cells 148

matrix 144

wound healing 129–54

agents aVecting growth factors/growth factor
receptors 153–4

angiogenesis inhibition 153

anticytoskeletal agents 148–9

antiinXammatory treatment 148

antimetabolic agents 149–53

antimigration agents 148–9

antiproliferative agents 149–53

antiscarring therapies 147–8

cell division reduction 149

central events 132–4, 135, 136, 137, 138–9,

140–1, 142–3

completion of process 146

early events 131

endothelial cells 139

epithelial cells 139, 142–3

extracellular matrix contraction 134, 135, 136,

137, 138

Wbroblasts 132–4, 135, 136, 138, 140–1

growth factors 146

immunosuppression 148

inXammatory cells 131

late events 143–6

matrix metalloproteinase 139

maturation phase 139

modulation 147–54

reepithelialization 139, 142–3, 144

remodelling phase 139

response 130

ribozymes 154

switching-oV 146

xanthine dehydrogenase 414

xanthine oxidase 201, 202, 414

superoxide generation 290

zymogens 322

zymography 146

458 Index

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